In recent years, the concept that allergic conditions such as bronchial asthma are fundamentally diseases of chronic inflammation has been established, and accumulation of eosinophils at local sites of inflammation is considered to be a major feature thereof (for example, see Busse, W. W. J. Allergy Clin. Immunol. 1998, 102, S17-S22; Fujisawa, T. Gendai Iryou 1999, 31, 1297). For example, administration of anti-adhesion molecule (ICAM-1) antibodies in monkey asthma models inhibits accumulation of eosinophils and suppresses late asthmatic symptoms, suggesting the importance of eosinophils in allergic conditions (Wegner, C. D. et al. Science, 1990, 247, 456).
Eotaxins have been identified as specific chemotactic factors inducing accumulation and/or migration of eosinophils (for example, see Jose, P. J., et al. J. Exp. Med. 1994, 179, 881; Garcia-Zepda, E. A. et al. Nature Med. 1996, 2, 449; Ponath, P. D. et al. J. Clin. Invest. 1996, 97, 604; Kitaura, M. et al. J. Biol. Chem. 1996, 271, 7725). It has also been demonstrated that eotaxins bind to CCR3 expressed on eosinophils, exhibiting an effect of promoting accumulation and/or migration of eosinophils. In addition, chemotactic factors such as eotaxin-2, RANTES (abbreviation for Regulated on Activation, Normal T-cell Expressed and Secreted) antibodies, MCP-2 (abbreviation for Monocyte Chemoattractant Protein-2), MCP-3 (abbreviation for Monocyte Chemoattractant Protein-3), MCP-4 (abbreviation for Monocyte Chemoattractant Protein-4) and the like are also known to exhibit effects similar to those of eotaxins via CCR3, although their potency is weaker than that of eotaxins (for example, see Kitaura, M. et al. J. Biol. Chem. 1996, 271, 7725; Daugherty, B. L. et al. J. Exp. Med. 1996, 183, 2349; Ponath, P. D. et al. J. Exp. Med. 1996, 183, 2437; Hiath, H. et al. J. Clin. Invest. 1997, 99, 178; Patel, V. P. et al. J. Exp. Med. 1997, 185, 1163; Forssmann, U. et al. J. Exp. Med. 185, 2171, 1997).
The reported effects of eotaxins on eosinophils include not only inducing migration of eosinophils, but also effects related to eosinophil activation, such as augmenting expression of adhesion molecule receptor (CD11b) (for example, see Tenscher, K. et al. Blood, 1996, 88, 3195), accelerating production of active oxygen (for example, see Elsner, J. et al. Eur. J. Immunol. 1996, 26, 1919), and promoting release of EDN (Eosinophil-Derived Neurotoxin) (see El-Shazly, et al. Int. Arch. Allergy Immunol. 1998, 117 (suppl.1), 55). Eotaxins have also been reported to accelerate liberation of eosinophils and their precursors from the bone marrow into the blood (for example, see Palframan, R. T. et al. Blood 1998, 91, 2240).
Numerous reports indicate that eotaxins and CCR3 play important roles in allergic conditions such as bronchial asthma. For example, it has been reported that infiltration of eosinophils is suppressed by anti-eotaxin antibodies in mouse asthma models (Gonzalo, J.-A. et al. J. Clin. Invest. 1996, 98, 2332), that infiltration of eosinophils is suppressed by anti-eotaxin antiserum in mouse cutaneous allergy models (Teixeira, M. M. et al. J. Clin. Invest. 1997, 100, 1657), that formation of pulmonary granulomas is suppressed by anti-eotaxin antibodies in mouse models (see Ruth, J. H. et al. J. Immunol. 1998, 161, 4276), that infiltration of eosinophils is suppressed in eotaxin gene-deficient mouse asthma models and interstitial keratitis models (see Rothenberg, M. E. et al. J. Exp. Med. 1997, 185, 785), that expression of eotaxins and CCR3 is augmented on both the genetic and protein level in asthmatic bronchi compared to healthy controls (see Ying, S. et al. Eur. J. Immunol. 1997, 27, 3507), and that eotaxin expression is augmented in nasal subepithelial tissue of chronic sinusitis patients (Am. J. Respir. Cell Mol. Biol. 1997, 17, 683).
Also, based on reports that eotaxins are abundantly expressed at sites of inflammation in the inflammatory bowel diseases of ulcerative colitis and Crohn's disease (see Garcia-Zepda, E. A. et al. Nature Med. 1996, 2, 449), it is believed that eotaxins also play an important role in such inflammatory conditions.
These data strongly suggest that eotaxins, via CCR3-mediated accumulation and activation of eosinophils at lesion sites, are intimately involved in the onset, progression or sustaining of diseases wherein eosinophils are closely associated with developing lesions, including, for example, allergic conditions such as bronchial asthma, allergic rhinitis, atopic dermatitis, urticaria, contact dermatitis or allergic conjunctivitis, inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, and eosinophilia, eosinophilic gastroenteritis, eosinophilic enteropathy, eosinophilic fasciitis, eosinophilic granuloma, eosinophilic pustular folliculitis, eosinophilic pneumonia or eosinophilic leukemia. In addition, since CCR3 is expressed not only on eosinophils but also on basophils and Th2 lymphocytes, and eotaxins induce intracellular calcium ion concentration increase and migration of these cells, it is believed that eotaxins and CCR3 are involved in the onset, progression and sustaining of diseases associated with these cells, such as allergic conditions, also via accumulation and activation of basophils and Th2 lymphocytes (for example, see Sallusto, F. et al. Science 1997, 277, 2005; Gerber, B. O. et al. Current Biol. 1997, 7, 836; Sallusto, F. et al. J. Exp. Med. 1998, 187, 875; Uguccioni, M. et al. J. Clin. Invest. 1997, 100, 1137; Yamada, H. et al. Biochem Biophys. Res. Commun. 1997, 231, 365).
Consequently, compounds which inhibit binding of CCR3 to CCR3 ligands such as eotaxins, or in other words CCR3 antagonists, should inhibit the effects of the CCR3 ligands on target cells and are therefore expected be useful as therapeutic and/or prophylactic agents for allergic conditions and inflammatory bowel disease. Yet, no agents having such activity have been known.
Moreover, it has also been reported that HIV-1 (Human Immunodeficiency Virus-1) may utilize CCR3 to infect host cells, and therefore CCR3 antagonists are also expected to be useful as therapeutic or prophylactic agents for AIDS (Acquired Immune Deficiency Syndrome) caused by HIV infection (for example, see Choe, H. et al. Cell 1996, 85, 1135; Doranz, B. J. et al. Cell 1996, 85, 1149).
Recently, piperidine derivatives (see Patent Specification No. WO9802151, Patent Specification No. WO9804554, Patent Specification No. WO0029377, Patent Specification No. WO0031033, Patent Specification No. WO0035449, Patent Specification No. WO0035451, Patent Specification No. WO0035452, Patent Specification No. WO0035453, Patent Specification No. WO0035454, Patent Specification No. WO0035876, Patent Specification No. WO0035877, Patent Specification No. WO0051607, Patent Specification No. WO0051608, Patent Specification No. WO0051609, Patent Specification No. WO0051610, Patent Specification No. WO0053600, Patent Specification No. WO0058305, Patent Specification No. WO0059497, Patent Specification No. WO0059498, Patent Specification No. WO0059502, Patent Specification No. WO0059503, Patent Specification No. WO0076511, Patent Specification No. WO0076512, Patent Specification No. WO0076513, Patent Specification No. WO0076514, Patent Specification No. WO0076972, Patent Specification No. WO0076973, Patent Specification No. WO0105782, Patent Specification No. WO0114333, Patent Specification No. WO0164216, Patent Specification No. WO0177101, Patent Specification No. WO0192227, Patent Specification No. WO0198268, Patent Specification No. WO0198269, Patent Specification No. WO0198270, Patent Specification No. WO0202525, Patent Specification No. WO0204420), piperazine derivatives (see Patent Specification No. EP0903349, Patent Specification No. WO0034278, Patent Specification No. WO0102381) and other low molecular compounds (see Patent Specification No. WO9955324, Patent Specification No. WO9955330, Patent Specification No. WO0004003, Patent Specification No. WO0027800, Patent Specification No. WO0027835, Patent Specification No. WO0027843, Patent Specification No. WO0031032, Patent Specification No. WO0041685, Patent Specification No. WO0053172, Patent Specification No. WO0109088, Patent Specification No. WO0128987, Patent Specification No. WO0129000), have been reported to exhibit antagonism against CCR3. However, these compounds differ from the compounds of the invention.
Patent Specification No. WO0107436 and Patent Specification No. WO9937304 describe oxopiperazine derivatives having inhibiting activity on Factor Xa, but they do not specifically mention the piperidine derivatives of the invention, nor is it known whether these oxopiperazine derivatives exhibit competitive inhibition for CCR3. Patent Specification No. WO0132615 and Patent Specification No. WO0268409 describe N-substituted piperidine derivatives having NMDA/NR2B antagonism, but they do not specifically mention the 4,4-(disubstituted)piperidine derivatives of the invention, nor is it known whether these N-substituted piperidine derivatives exhibit competitive inhibition for CCR3.
It is an object of the present invention to provide low molecular compounds having activity which inhibits binding of CCR3 ligands to CCR3 on target cells, i.e. CCR3 antagonists.
It is another object of the invention to provide therapeutic and/or prophylactic agents for diseases in which a causal factor is binding of a CCR3 ligand to CCR3 on target cells.